Liquid-phase organic synthesis of imidazo[1,2-a]pyridine derivatives using PEG-supported sulfonyl chloride

Article abstract of DOI:10.3184/030823408X320638

Reaction of PEG-bound sulfonic acid with thionyl chloride formed the difunctionalised PEG-supported sulfonyl chloride, which was treated with α-hydroxyketones, followed by treatment with 2-aminopyridine in the presence of potassium carbonate efficient to afford imidazo[1,2-a]pyridines in good yields with a facile work-up procedure.

Full text of DOI:10.3184/030823408X320638

JOURNAL OF CHEMICAL RESEARCH 2008
MAY, 289–291
RESEARCH PAPER 289
Liquid-phase organic synthesis of imidazo[1,2-a]pyridine derivatives
using PEG-supported sulfonyl chloride
Chao-Li Wang, Shou-Ri Sheng*, Hu Chen, Xiao-Ling Liu and Ming-Zhong Cai
College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, 330027, P. R. China
Reaction of PEG-bound sulfonic acid with thionyl chloride formed the difunctionalised PEG-supported sulfonyl
chloride, which was treated with D-hydroxyketones, followed by treatment with 2-aminopyridine in the presence of
potassium carbonate efficient to afford imidazo[1,2-a]pyridines in good yields with a facile work-up procedure.
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use of PEG-bound sulfonic acid for the preparation of 1,1-
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To optimise the reaction conditions, several solvents like
dichloromethane, acetonitrile, N,NꢀGLPHWK\OIRUPDPLGHꢁ RUꢁ
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corresponding imidazo[1,2-a@S\ULGLQHVꢁ4 in moderate to good
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group or an electron-donating group on the aromatic ring
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Table 1 The yields of imidazo[1,2-a]pyridines 4
Entry
R1
R2
Products
Yield/%a
1
2
C6H5
H
H
4a
4a
4a
4a
4b
4c
4d
4e
4f
80
79b
80c
78d
81
78
75
74
75
70
73
60
C6H5
3
C6H5
C6H5
H
4
H
5
p-CH3C6H4
p-CH3OC6H4
p-ClC6H4
p-BrC6H4
p-FC6H4
p-NO2C6H4
2-furyl
H
6
H
7
H
8
H
9
H
10
11
12
H
4g
4h
4i
H
C6H5
CH3
aYields refer to the isolated pure products based on PEG-bound
disulfonyl chloride. bWith the first regenerated resin. cWith the
second regenerated resin. dWith the fourth regenerated resin.
NH2
R1COCH(OH)R2
R1
R2
O
S
O
R2
N
SOCl2
N
R1
SO3H
SO2Cl
O
N
DMF, rt, 16 h
CH2Cl2 / Et3N
reflux, 24 h
K2CO3
O
CH3CN
reflux, 10 h
PEG
1
2
3
4
Scheme 1
* Correspondent. E-mail: shengsr@jxnu.edu.cn

290 JOURNAL OF CHEMICAL RESEARCH 2008
1 H), 7.14–7.16 (m, 1 H), 6.98 (d, J = 8.8 Hz, 2 H), 6.76 (t, J = 6.7 Hz,
ꢃꢁ+ꢇꢂꢁꢑꢅꢋꢍꢁꢆVꢂꢁꢑꢁ+ꢇꢒꢁ,5ꢁꢆ.%UꢇꢓꢁȞꢁ ꢁꢑꢃꢑꢄꢂꢁꢑꢉꢑꢃꢂꢁꢄꢋꢊꢄꢂꢁꢃꢏꢑꢈꢂꢁꢃꢏꢉꢉꢂꢁ
1510, 1445, 1376, 1080, 842, 766, 690 cm-1.
2-(4-Chlorophenyl)imidazo[1,2-a]pyridine (4d)ꢓꢁ <HOORZꢁ VROLGꢒꢁ
m.p. 202–203°C (Lit.24 m.p. 205–206°C); 1+ꢁ 105ꢓꢁ įꢁ ꢁ ꢋꢅꢃꢄꢁ ꢆGꢂꢁ
J = 6.8 Hz, 1 H), 7.89 (d, J = 8.8 Hz, 2 H), 7.83 (s, 1 H), 7.62 (d,
J = 8.9 Hz, 1 H), 7.42 (d, J = 8.8 Hz, 2 H), 7.18 (t, J = 7.1 Hz, 1 H),
6.76 (t, J ꢁꢏꢅꢋꢁ+]ꢂꢁꢃꢁ+ꢇꢒꢁ,5ꢁꢆ.%UꢇꢓꢁȞꢁ ꢁꢑꢉꢑꢑꢂꢁꢃꢏꢑꢍꢂꢁꢃꢏꢉꢉꢂꢁꢃꢍꢃꢄꢂꢁꢃꢈꢊꢉꢂꢁ
1401, 1172, 1080, 836, 770 cm-1.
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PEG-bound sulfonic acid 1ꢁDJDLQꢁE\ꢁWUHDWPHQWꢁZLWKꢁFRQFꢅꢁ+&Oꢅꢁ
7KHUHIRUHꢁWKHꢁFRYHUHGꢁSRO\PHULFꢁVXOIRQLFꢁDFLGꢁ1 can be used
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in Table 1 (entries 1–4).
2-(4-Bromophenyl)imidazo[1,2-a]pyridine (4e)ꢓꢁ <HOORZꢁ VROLGꢒꢁ
m.p. 215–217°C (Lit.31 m.p. 215–216°C); 1+ꢁ 105ꢓꢁ įꢁ ꢁ ꢋꢅꢃꢃꢁ ꢆGꢂꢁ
J = 6.8 Hz, 1 H), 7.85–7.83 (m, 2 H), 7.82 (s, 1 H), 7.63 (d, J = 9.0 Hz,
1 H), 7.57–7.55 (m, 2 H), 7.20–7.18 (m, 1 H), 6.79 (t, J = 6.8 Hz,
ꢃꢁ+ꢇꢒꢁ,5ꢁꢆ.%UꢇꢓꢁȞꢁ ꢁꢑꢉꢑꢈꢂꢁꢃꢏꢑꢈꢂꢁꢃꢏꢉꢃꢂꢁꢃꢍꢃꢉꢂꢁꢃꢈꢊꢈꢂꢁꢃꢈꢉꢃꢂꢁꢃꢃꢏꢐꢂꢁꢃꢉꢋꢉꢂꢁ
835, 772 cm-1.
2-(4-Fluorophenyl)imidazo[1,2-a]pyridine (4f)ꢓꢁ<HOORZꢁVROLGꢒꢁPꢅSꢅꢁ
163–164°C (Lit.32 m.p. 165–166°C); 1+ꢁ105ꢓꢁįꢁ ꢁꢋꢅꢃꢄꢁꢆGꢂꢁJ = 6.8 Hz,
1 H), 7.94–7.91 (m, 2 H), 7.81 (s, 1 H), 7.63 (d, J = 9.1 Hz, 1 H),
7.17–7.11 (m, 3 H), 6.78 (t, J ꢁꢏꢅꢋꢁ+]ꢂꢁꢃꢁ+ꢇꢒꢁ,5ꢁꢆ.%UꢇꢓꢁȞꢁ ꢁꢑꢉꢑꢄꢂꢁ
1634, 1600, 1513, 1475, 1401, 1169, 1080, 835, 772 cm-1.
2-(4-Nitrophenyl)imidazo[1,2-a]pyridine (4g)ꢓꢁ <HOORZꢁ VROLGꢒꢁ
m.p. 266–267°C (Lit.30 m.p. 269°C); 1+ꢁ105ꢓꢁįꢁ ꢁꢋꢅꢄꢐꢁꢆGꢂꢁJ = 8.9 Hz,
2 H), 8.17 (d, J = 6.8 Hz, 1 H), 8.13 (d, J = 8.9 Hz, 2 H), 8.01 (s, 1 H),
7.67 (d, J = 9.0 Hz, 1 H), 7.25–7.23 (m, 1 H), 6.84 (t, J = 6.8 Hz,
ꢃꢁ+ꢇꢒꢁ,5ꢁꢆ.%UꢇꢓꢁȞꢁ ꢁꢑꢉꢑꢊꢂꢁꢃꢏꢈꢉꢂꢁꢃꢍꢐꢐꢂꢁꢃꢍꢄꢉꢂꢁꢃꢍꢉꢉꢂꢁꢃꢃꢃꢉꢂꢁꢃꢉꢋꢄꢂꢁꢋꢍꢃꢂꢁ
744, 696 cm-1.
2-(2-Furyl)imidazo[1,2-a]pyridine (4h)ꢓꢁ %URZQꢁ VROLGꢒꢁ PꢅSꢅꢁ ꢐꢃ±
92°C (Lit.24 m.p. 90–91°C); 1+ꢁ105ꢓꢁįꢁ ꢁꢋꢅꢃꢃꢁꢆGꢂꢁJ = 6.8 Hz, 1 H),
7.80 (s, 1 H), 7.63 (d, J = 9.0 Hz, 1 H), 7.47 (d, J = 1.7 Hz, 1 H), 7.19
(t, J = 7.8 Hz, 1 H), 6.90 (d, J = 3.2 Hz, 1 H), 6.79 (t, J = 6.8 Hz,
1 H), 6.51–6.52 (dd, J ꢁꢑꢅꢍꢂꢁꢃꢅꢋꢁ+]ꢂꢁꢃꢁ+ꢇꢒꢁ,5ꢁꢆ.%UꢇꢓꢁȞꢁ ꢁꢑꢉꢋꢐꢂꢁꢃꢏꢑꢏꢂꢁ
1608, 1486, 1236, 1082, 965, 745, 690 cm-1.
3-Methyl-2-phenylimidazo[1,2-a]pyridine (4i): Colourless solid;
m.p. 91–92°C (Lit.33 m.p. 90–91°C); 1+ꢁ105ꢓꢁįꢁ ꢁꢊꢅꢐꢃꢁꢆGꢂꢁJ = 6.8 Hz,
1 H), 7.81–7.779 (m, 2 H), 6.66–6.64 (d, J = 9.0 Hz, 1 H), 7.48–7.45
(m, 2 H), 7.36–7.34 (m, 1 H), 7.19–7.16 (t, J = 7.9 Hz, 1 H), 6.87–
6.84 (t, J = 6.8 Hz, 1 H), 2.65 (s, 3 H); IR (KBr): Ȟꢁ ꢁꢑꢃꢑꢉꢂꢁꢑꢉꢑꢄꢂꢁ
1633, 1608, 1510, 1444, 1081, 920, 741, 693 cm-1.
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preparation of imidazo[1,2-a@S\ULGLQHVꢁ IURPꢁ WKHꢁ UHDFWLRQꢁ RIꢁ
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K\GUR[\NHWRQHVꢂꢁIROORZHGꢁE\ꢁWUHDWPHQWꢁZLWKꢁꢄꢀDPLQRS\ULGLQHꢁ
LQꢁ WKHꢁ SUHVHQFHꢁ RIꢁ SRWDVVLXPꢁ FDUERQDWHꢁ ZDVꢁ VXFFHVVIXOO\ꢁ
carried out.
Experimental
0HOWLQJꢁSRLQWVꢁZHUHꢁGHWHUPLQHGꢁRQꢁ;4 melting point apparatus and are
uncorrected. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra
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CDCl3 as the solvent and TMS as an internal standard. FT–IR spectra
ZHUHꢁWDNHQꢁIURPꢁDꢁ3HUNLQꢀ(OPHUꢁ63ꢁ2QHꢁ)7±,5ꢁVSHFWURSKRWRPHWHUꢅꢁ
PEG-bound sulfonic acid prepared according to our report method.27
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Preparation of PEG-bound sulfonyl chloride 2; general procedure
Under a nitrogen atmosphere, to PEG 4000 disulfonic acid 1 (10.0 g,
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ZDVꢁUHPRYHGꢁin vacuo and the crude product dissolved in hot propan-
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Et2O (50 ml), and then dried in vacuoꢁWRꢁDIIRUGꢁ3(*ꢀERXQGꢁVXOIRQ\Oꢁ
chloride 2ꢁDVꢁDꢁZKLWHꢁVROLGꢁꢆꢐꢅꢍꢉꢁJꢂꢁꢐꢍꢌꢇꢅꢁ1H NMR (400 MHz; CDCl3)
įꢁꢑꢅꢑꢐ±ꢑꢅꢋꢐꢁꢆPꢂꢁ3(*ꢁCH2), 4.23 (t, J = 4.6 Hz, 4 H, CH2OAr), 7.08
(d, J = 8.9 Hz, 4 H, ArH), 7.95 (d, J = 8.9 Hz, 4 H, ArH). FT–IR
ꢆ.%UꢇꢁȣꢁꢑꢉꢑꢄꢂꢁꢄꢐꢈꢈꢂꢁꢃꢏꢉꢉꢂꢁꢃꢍꢈꢍꢂꢁꢃꢑꢊꢃꢂꢁꢃꢃꢉꢍꢂꢁꢋꢄꢈꢁFP-1.
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Natural Science Foundation of China (No. 20562005) and NSF
of Jiangxi Province (No. 0620021 and No. 2007GZW0185).
Preparation of imidazo[1,2-a]pyridines (4a–i); General procedure
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2 (4.35 g, 1.0 mmol) and Et3N (2.0 mmol), and the reaction mixture
ZDVꢁKHDWHGꢁDWꢁUHÀX[ꢁIRUꢁꢄꢈꢁKꢁXQGHUꢁDQꢁ12 atmosphere. The solvent
ZDVꢁUHPRYHGꢁin vacuo, and the crude product dissolved in hot propan-
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then dried in vacuoꢁWRꢁDIIRUGꢁ3(*ꢀERXQGꢁĮꢀVXOIRQ\OR[\ꢁNHWRQHꢁ3 as a
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DQGꢁꢄꢀDPLQRS\ULGLQHꢁꢆꢑꢅꢉꢁPPROꢇꢁLQꢁ0H&1ꢁꢆꢄꢉꢁPOꢇꢂꢁ.2CO3 (1.24 g,
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10 h under an N2ꢁDWPRVSKHUHꢅꢁ7KHQꢁWKHꢁVROYHQWꢁZDVꢁUHPRYHGꢁXQGHUꢁ
YDFXXPꢂꢁDQGꢁGLHWK\OꢁHWKHUꢁꢆꢄꢉꢉꢁPOꢇꢁZDVꢁDGGHGꢁZLWKꢁYLJRURXVꢁVWLUULQJꢁ
DQGꢁ WKHꢁ PL[WXUHꢁ ZDVꢁ FRROHGꢁ WRꢁ ꢉƒ&ꢅꢁ 7KHꢁ UHFRYHUHGꢁ 3(*ꢀERXQGꢁ
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FROGꢁGLHWK\OꢁHWKHUꢁꢆꢄꢁîꢁꢄꢉꢁPOꢇꢅꢁ7KHꢁ¿OWUDWHꢁZDVꢁZDVKHGꢁZDWHUꢁꢆHDFKꢁRIꢁ
10 ml), dried over sodium sulfate. After evaporation of the solvent,
WKHꢁ UHVLGXHꢁ ZDVꢁ VXEMHFWHGꢁ WRꢁ FROXPQꢁ FKURPDWRJUDSK\ꢁ ꢆVLOLFDꢁ JHOꢒꢁ
hexane-EtOAc, 3:1) to afforded pure imidazo[1,2-a@S\ULGLQHꢁ4.
2-Phenylimidazo[1,2-a]pyridine (4a): Colourless solid; m.p. 131–
132°C (Lit.25 m.p. 130–32°C); 1+ꢁ105ꢓꢁįꢁ ꢁꢋꢅꢃꢑꢁꢆGꢂꢁJ = 6.8 Hz,
1 H), 7.96 (d, J = 7.2 Hz, 2 H), 7.86 (s, 1 H), 7.63 (d, J = 9.0 Hz,
1 H), 7.44 (t, J = 7.2 Hz, 2 H), 7.33 (t, J = 7.2 Hz, 1 H), 7.18
(t, J = 7.5 Hz, 1 H), 6.78 (t, J ꢁꢏꢅꢊꢁ+]ꢂꢁꢃꢁ+ꢇꢒꢁ,5ꢁꢆ.%UꢇꢓꢁȞꢁ ꢁꢑꢉꢑꢑꢂꢁ
1633, 1600, 1510, 1440, 1080, 922, 745, 690 cm-1.
Received 3 February 2008; accepted 3 May 2008
Paper 08/5085 doi: 10.3184/030823408X320638
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2-(4-Methylphenyl)imidazo[1,2-a]pyridine (4b)ꢓꢁ3DOHꢁ\HOORZꢁVROLGꢒꢁ
m.p. 143–144°C (Lit.24 m.p. 144–145°C); 1+ꢁ 105ꢓꢁ įꢁ ꢁ ꢋꢅꢃꢄꢁ ꢆGꢂꢁ
J = 6.7 Hz, 1 H), 7.86 (d, J = 8.2 Hz, 2 H), 7.83 (s, 1 H), 7.64 (d,
J = 9.0 Hz, 1 H), 7.25 (d, J = 8.2 Hz, 2 H), 7.16 (t, J = 7.9 Hz, 1 H),
6.77 (t, J ꢁꢏꢅꢊꢁ+]ꢂꢁꢃꢁ+ꢇꢂꢁꢄꢅꢑꢋꢁꢆVꢂꢁꢑꢁ+ꢇꢒꢁ,5ꢁꢆ.%UꢇꢓꢁȞꢁ ꢁꢑꢃꢑꢄꢂꢁꢑꢉꢑꢍꢂꢁ
2875, 1633, 1600, 1513, 1454, 1378, 1082, 990, 828, 745 cm-1.
2-(4-Methoxyphenyl)imidazo[1,2-a]pyridine (4c)ꢓꢁ <HOORZꢁ VROLGꢒꢁ
m.p. 133–134°C (Lit.30 m.p. 136°C); 1+ꢁ105ꢓꢁįꢁ ꢁꢋꢅꢉꢋꢁꢆWꢂꢁJ = 6.7 Hz,
1 H), 7.88 (d, J = 8.8 Hz, 2 H), 7.80 (s, 1 H), 7.62 (d, J = 9.0 Hz,
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